#5865 BET INHIBITION DIMINISHES CELLULAR SENESCENCE IN CULTURED TUBULAR EPITHELIAL CELLS

Abstract

Abstract Background and Aims Chronic kidney disease (CKD) can be considered an age-related disorder. Recent studies have shown the involvement of the activation of cellular senescence mechanisms in the kidney and aging. Intensive research to develop pharmacological approaches targeting cellular senescence is under investigation. Among novel therapeutic options, epigenetic drugs, such as bromodomain and extra terminal BET inhibitors, are being widely explored in proliferative, immune and chronic inflammatory diseases, including CKD. These drugs regulate transcription activation of cell cycle control and proinflammatory factors. There are not studies about the potential effect of BET inhibitors on cellular senescence in the kidney despite the fact that tubular epithelial cells are frequently implicated in kidney senescence. Method To study this, we evaluate the effect of JQ1, a BET inhibitor, on cellular senescence in primary cell culture of murine tubular epithelial cells (TECs) using Adriamycin as a senescence inducer verified by B-galactosidase assay. Next, we evaluated the effect of JQ1 on gene expression levels of cell cycle markers, components of senescence-associated secretory phenotype (SASP) as well as anti-apoptotic and antioxidant markers, all of them related to senescence program. Results Our results indicated that JQ1 significantly decreased Adriamycin-induced p21 gene upregulation, a primordial cell cycle arrest factor. This BET inhibitor also downregulated SAPS genes, such as Tgfb1, Il1b, Ctgf, Ccl2 and Il6 overexpression in Adriamycin-treated tubular cells. Likewise, anti-apoptotic Bcl-xl and antioxidant factors Cat, Hmox-1, Nox-4 and Nrf2 mRNA levels were significantly restored by JQ1. Conclusion In conclusion, the present study highlights the use of JQ1 as a therapeutic option to ameliorate tubular cellular senescence-associated markers. These data support the potential use of BET inhibitors in chronic kidney diseases.